1. Field of the Invention
The invention relates to the methods for preparation of olanzapine polymorphic Form I. The invention also relates to the new mixed solvates of olanzapine which are valuable intermediates used in the preparation of pure olanzapine polymorphic Form I.
2. Background of the Invention
Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3b][1,5]benzodiazepine is a potent antipsychotic agent. Olanzapine as a free base or its hydrochloride salt is an active ingredient of pharmaceutical preparations used in the treatment of disorders of the central nervous system.
Olanzapine was described for the first time in the European Patent Application EP 0454436 A1. One of the disclosed methods for preparation of olanzapine (Example 1, Point 4) is based on condensation of 4-amine-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine with N-methylpiperazine carried out in dimethylsulfoxide and toluene. At the final stage of the reaction, water is added and a crude product thus isolated is crystallized from acetonitrile.
In the second method (Example 2, Point 3), a crude product is obtained by cyclization of 1-{[2-amine-aniline)-5-metyhlthiophen-3-yl]carbonyl}-4-methyl-piperazine carried out in N-methylpiperazine and anisole, isolated by treating with ammonia, isopropanol and ethyl acetate and finaly purified. Purification is performed by column chromatography with the use of Florisil eluted with ethyl acetate and the product is further crystallized from acetonitrile.
Both methods disclosed in EP 0454436 A1 lead to obtain olanzapine in a pure crystalline form which is characterized by a specific melting point, NMR spectra (1H and 13C) and mass spectrum.
The European Patent Application EP 0733635 A1 discloses that olanzapine can exist in two different polymorphic crystalline forms which differ from each other by their stability, physical properties and spectral characteristics. Polymorph as prepared by the procedures according to EP 0454436 A1 comprising the crystallization from acetonitrile has been denominated Form I and it has been described to be metastable and not suitable for commercial use in pharmaceutical formulations such as tablets due to its color, which changes over time on exposure to air.
In EP 0733635 A1, a more thermodynamically stable second polymorph of olanzapine is claimed. Accordingly, olanzapine polymorphic Form II is obtained by suspending crude olanzapine in ethyl acetate in anhydrous conditions and crystallization from this solution. The occurrence of olanzapine in two different polymorphic forms has been confirmed by X-ray powder diffraction patterns which are characterized by different interplanar spacings (d) and relative intensities (I/I0).
Thus, the practical process for the preparation of olanzapine described in EP 0454436 A1 and in the subsequent documents of the prior art, for example in WO 96/38151 and WO 02/18390, comprises the condensation of a molar excess of N-methylpiperazine with 4-amine-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride in the mixture of dimethylsulfoxide and toluene. When the reaction is completed, excess of water and/or another hydroxylic solvent is added to remove unreacted substrates and to isolate a crude product. After cooling, the crude product is separated in the form of solvate. Depending on the method used for crystallization of the intermediate solvate, polymorphic form I or II of olanzapine is obtained.
However, the methods of the prior art are rather difficult to reproduce and often do not lead to obtaining the anticipated olanzapine polymorphic form.
For example, following the procedure of Preparation 1 of EP 0828494 (WO 96/38151), the obtaining of polymorphic Form II is declared. However, the X-ray powder diffraction pattern of the product matches with that of olanzapine Form I as claimed in EP 0733635 A1.
On the other hand, in WO 96/38151, preperation methods are given for a polymorph defined as olanzapine Form I, consisting in the crystallization of crude product from acetone (Preparation 6), butyl acetate (Preparation 7), t-butanol (Preparation 8) and in transformation of Form I carried out in toluene.
It is fair to assume that olanzapine Form II of WO 96/38151 is the polymorph denominated Form I in EP 0733635.
This conclusion has been evidenced in a laboratory practice, where the use of any solvent, such as acetonitrile, tetrahydrofuran, acetone, toluene or ethyl acetate, for crystallization of crude olanzapine always resulted in crystalline Form II, identified by X-ray powder diffraction patterns described in EP 0733635. The only one solvent enabling to obtain olanzapine polymorphic Form I by crystallization of crude olanzapine or its crystalline Form II, is methylene chloride.
The use of intermediate solvate of olanzapine with methylene chloride for obtaining anhydrous Form I of olanzapine is disclosed in U.S. Pat. No. 5,637,584. The solvate of olanzapine with methylene chloride is prepared by suspending technical grade olanzapine in methylene chloride, heating and stirring the mixture at 30° C., chilling the mixture to 5° C. and isolating the product.
According to U.S. Pat. No. 5,637,584, technical grade olanzapine may be defined as 2-methyl-4-(4-methyl-1-piperazinyl)10H-thieno[2,3-b][1,5]benzodiazepine when no specific solvate or polymorph is named. Typically, the technical grade olanzapine contains less than 5% undesired related substances and may be a mixed polymorph.
But, in a laboratory practice it is observed that olanzapine obtained by the methods of prior art, comprising the reaction of a molar excess of N-methylpiperazine with 4-amine-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine in organic solvent, eg. dimethylsulfoxide and toluene, and subsequent addition of water and/or hydroxylic solvent, usually contains much more than 5% of impurities; in some experiments the level of impurities exceeds 10-15%. As a consequence more than single, mostly at least triple, crystallization from different solvents is required to remove these impurities to obtain olanzapine of pharmaceutical grade. Optionally one additional crystallization is needed to transform olanzapine into a desired polymorphic form.
As concerns the method for preparing a technical grade olanzapine, U.S. Pat. No. 5,637,584 especially refers to U.S. Pat. No. 5,229,382. Moreover, according to U.S. Pat. No. 5,637,584, olanzapine prepared by a method described in U.S. Pat. No. 5,229,382 is a crude product exhibiting a colour, which colour is difficult to be removed with typically used methods (eg. with the aid of charcoal). This undesired coloration is a result of impurities content.
In Preparation 4 of WO 96/38151, for obtaining a technical grade olanzapine, crude olanzapine is recrystallized from toluene. After drying in vacuo at 50° C., such obtained technical grade olanzapine requires further recrystallization from ethyl acetate/toluene/methanol to give a methanol solvate, which is converted, upon drying, to an anhydrous technical grade olanzapine.
Thus, a technical grade olanzapine obtained as above, still contains undesired related substances and may be a mixture of polymorphs, so it needs further processing to transform it into crystalline pure polymorphic Form I. The method for transforming olanzapine obtained in Preparation 4 of WO 96/38151 into olanzapine Form I comprises suspending crude olanzapine in methylene chloride, stirring the mixture at ambient temperature, chilling the filtrate and evaporating ¾ of solvent. Then, into the thick paste prechilled methylene chloride is mixed, the solid product is isolated and dried at first on the air and then at 50° C. in a vaccum oven. Product obtained is olanzapine Form I and CH2Cl2 solvate. Only re-drying this product at 50° C. gives pure polymorphic Form I of olanzapine.
Independently, the use of methylene chloride for crystallization of olanzapine in polymorphic Form I via intermediate monohydrate-1 and dihydrate-2 forms of olanzapine has been described in an International Patent Publication WO 02/18390. Intermediate hydrates are formed by adding water to the reaction mixture formed after completion of the reaction of 4-amine-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride with N-methyl-piperazine in the mixture of dimethylsulfoxide and toluene, then by cooling and isolating the precipitate. The degree of hydration of the resulting intermediates depends on time of drying of the samples. Neither monohydrate-1 nor dihydrate-2 contains methylene chloride or dimethylsulfoxide. These intermediates are transformed into olanzapine polymorphic Form I by heating to reflux in methylene chloride. The process according to WO 02/18390 is a laborious one, as it needs isolating the intermediate hydrates and controlling the parameters of their drying, on the contrary the product may be non-homogenous.
Teaching of the above-mentioned documents as well as the failure of the attempts to reproduce the prior art methods for preparation of olanzapine polymorphic Form I free of other polymorphs and pseudopolymorphs, have proned us to find an efficient method for isolation and purification of olanzapine Form I, which method would be suitable for technical scale processes.